B cells expressing the transcription factor T-bet have emerged as participants in a number of protective and pathogenic immune responses. later recognized to express T-bet 47. These memory cells are required to generate an IgG response to secondary challenge 46, and bone marrow IgM+ antibody secreting cells, which may arise from IgM+T-bet+ precursors, protect from fatal challenge 48. Recently, Kenderes et al. confirmed and extended these initial observations, showing that stimulation and were necessary for maintaining reduced viral titers 49. Similarly, Barnett et al. found that T-bet-expressing B cells are necessary for lymphocytic choriomeningitis virus (LCMV)-specific WEHI-9625 IgG2a production, and are dispensable during acute infection but necessary for control of chronic WEHI-9625 infection 39. Interestingly, serum transfer of virus-specific IgG2a to mice with T-bet-deficient B cells was insufficient to return chronic viral loads to low levels, suggesting the viral control afforded by T-bet+ B cells is only partly due to IgG2a production 39. Thus, T-bet+ B cells are generated by and critical for protective responses to intracellular bacterial and viral infections. In 2011, two independent but jointly published studies identified a splenic B cell subset continuously enlarged with advancing WEHI-9625 age in several strains of mice and F1 hybrids; these were therefore coined Age-Associated B Rabbit polyclonal to ZKSCAN3 cells (ABCs; 27, 28). Hao et al. identified ABCs as CD23?CD21/35? cells that also lacked transitional and B1 markers 27, and Rubtsov et al. further described them as CD11c+ and expressing T-bet at the transcript level 28. Both groups demonstrated that ABCs display WEHI-9625 unique signaling characteristics: they respond with robust proliferation to TLR-7 and TLR-9 agonists, yet survive but fail to divide in response to B cell receptor (BCR) cross linking. These features distinguish ABCs from FO B cells, which briskly proliferate in response to B cell receptor (BCR) cross linking, as well as from MZ and TR cells, which die following BCR ligation. ABCs are further differentiated from FO, MZ, and TR subsets by their non-reliance on the homeostatic survival signals provided by B cell activating factor (BAFF; also known as B lymphocyte stimulator protein, or BLyS) via the BAFF receptor 27. The Rubtsov study made another key observation: ABC numbers expand earlier in autoimmune prone strains of mice compared to controls, suggesting involvement of ABCs in humoral autoimmunity 28. Indeed, these cells secrete autoantibodies and are required for kidney damage and death in lupus-prone mice 28, 31, 33. Heterogeneity of T-bet+ B cell phenotypes in mice The diverse studies mentioned above describe the emergence of atypical B cell subsets with common phenotypic characteristics following Th1-type infection, autoimmune disease onset, or aging; however, these cells have been variably defined by different research groups, and it remains unclear if the diverse descriptions of what are now considered T-bet+ B cells are due to the particular methods used in each study or natural phenotypic heterogeneity within this subset. The studies that first identified ABCs began to establish the particular phenotype of T-bet+ B cells, although discrepancies quickly arose. Hao et al. described diminished expression of CD23 and CD21 by ABCs, along with negative expression of B1 cell markers CD5 and CD43 and the myeloid marker CD11b. Based upon comparable expression of MHC-II and CD86 versus follicular B cells, they were considered to be non-activated 27. Conversely, Rubtsov et al. described low CD21 expression but primarily defined ABCs as expressing CD11b and CD11c, two integrins typically associated with the myeloid lineage. They further defined ABCs as expressing the B1 cell marker CD5, the plasma cell marker CD138, and a number of activation markers, including CD86 28. The anatomic localization of these cells was also disputed, as ABCs were identified in the spleen and blood by both groups, but were also found in the lymph nodes of mice aged more than two years by Rubtsov et al 27, 28. The relatively non-specific definition of these cells WEHI-9625 at this time likely contributed to the described disparities. While low to undetectable levels of the surface markers CD23 and CD21.